This invention relates to a hitherto unknown class of compounds which shows anti-inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of asthma and allergy; inflammatory diseases, such as arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn""s disease), uveitis, septic shock, and AIDS; proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, and acne; and osteoporosis.
Previously, a series of closely related aminobenzophenones (e.g. 4-(2-amino-4-nitrophenylamino)benzophenone) have been described (Hussein, F. A. et al, Iraqi J. Sci., 22, 54-66 (1981)). However, there is no description of their uses. WO 98/32730 discloses aminobenzophenone inhibitors of interleukin 1xcex2 (IL-1xcex2) and tumour necrosis factor xcex1 (TNF-xcex1) secretion in vitro, said compounds being potentially useful for treatment of inflammatory diseases in which the production of cytokines is involved in the pathogenesis, e.g. asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and atopic dermatitis. Furthermore the compounds of PCT/DK98/00008 were tested in vivo for anti-inflammatory properties in the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model, (De Young, L. M. et al., Agents Actions, 26, 335-341 (1989); Carlson, R. P. et al., Agents Actions, 17, 197-204 (1985); Alford, J. G. et al., Agents Action, 37, (1992); Stanley, P. L. et al., Skin Pharmacol, 4, 262-271 (1991)). In this chronic skin inflammation model the compounds had the same potency compared to the reference compound hydrocortisone.
The purpose of the present invention is to provide further pharmacologically active benzophenone derivatives and related compounds.
It has surprisingly been found that novel aminobenzophenone derivatives according to the general formula I are potent inhibitors of interleukin 1xcex2 (IL-1xcex2) and tumour necrosis factor xcex1 (TNF-xcex1) secretion in vitro, making them potentially useful for treatment of inflammatory diseases, in which the secretion and regulation of cytokines or more specifically interleukin 1xcex2 (IL-1xcex2) and tumour necrosis factor xcex1 (TNF-xcex1) are involved in the pathogenesis. The inhibition or down regulation of the cytokines is possibly due to an inhibition of MAP kinases. The preparation of structurally related aminobenzophenones useful as dyes for textiles is disclosed in Man-Made Text. India (1987), 30(6), 275-6; Man-Made Text. India (1986), 29(5), 224-30; and Man-Made Text. India (1985), 28(11), 425, 427-9, 431; an related aminobenzophenone is disclosed in JP 81-61259 as a reactant in the preparation of fluoran color formers.
The compounds of the present invention are represented by the general formula I 
wherein
R1 represents a substituent selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, xe2x80x94CONH2, phenyl, or nitro;
R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, xe2x80x94CONH2, phenyl, or nitro;
R3 represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, carbamoyl, (C1-C10)alkyl, (C2-C10)olefinic group, (C3-C8)monocyclic hydrocarbon group, (C1-C10)alkoxy, (C1-C10)alkylthio, (C1-C10)alkoxycarbonyl, or phenyl;
R4 represents hydrogen, (C1-C6)alkyl, (C2-C6)olefinic group, or (C3-C6)monocyclic hydrocarbon group;
R5 represents one or more, same or different substituents selected from the group consisting of hydrogen and R1;
X represents oxygen, sulphur, or Nxe2x80x94OH;
with the proviso that when X represents oxygen then R1, R2 and R5 together does not represent more than 8 fluorine substituents and with the proviso that the following compounds are not included in formula I:
2-Chloro-4xe2x80x2-(2-chlorophenylamino)benzophenone,
2-Chloro-4xe2x80x2-(phenylamino)benzophenone,
2-Hydroxy-4xe2x80x2-(phenylamino)benzophenone,
2-Hydroxy-4xe2x80x2-(4-hydroxyphenylamino)benzophenone,
2-Hydroxy-4xe2x80x2-(4-methoxyphenylamino)benzophenone,
2-Hydroxy-4xe2x80x2-(2-hydroxyphenylamino)benzophenone,
2-Hydroxy-4xe2x80x2-(2-methoxyphenylamino)benzophenone,
2-Methoxy-4xe2x80x2-(2-methoxyphenylamino)benzophenone, and
2-Methyl-4xe2x80x2-(4-methoxyphenylamino)benzophenone.
Preferred embodiments of the invention
In compounds of formula I R1 preferably represents a substituent selected from the group consisting of fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, and xe2x80x94CONH2;
R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, and (C1-C3)alkoxy.
R3 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, cyano, carboxy, and xe2x80x94CONH2.
R4 represents hydrogen, (C1-C4)alkyl, or (C2-C4)olefinic group;
X represents oxygen or sulphur;
R5 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, and xe2x80x94CONH2;
More preferably R1 represents a substituent selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
R3 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, methoxy, cyano, and carboxy;
R4 represents hydrogen, methyl, or ethyl;
R5 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, methyl, ethyl, and methoxy;
X represents oxygen;
The phenyl group of R1, R2, R3, and R5 may optionally be substituted, e.g. with hydroxy; amino; nitro; cyano; halogen, preferably fluoro, chloro, or bromo; methyl; or methoxy.
A preferred embodiment of the invention is the formula VII: 
wherein X, R1, R2, R3, R4, and R5 have the meanings specified above except that R2 does not represent hydrogen. Preferred compounds of formula VII are compounds wherein R2 represents a halogen atom, preferably chlorine.
Specific compounds of formula I or VII of the invention are:
2-[[3-Chloro-4-(2-methylbenzoyl)]phenylamino]benzonitrile (Compound 101),
2-Chloro-2xe2x80x2-methyl-4-(2-methyl-phenylamino)benzophenone (Compound 102),
2-Chloro-2xe2x80x2-methyl-4-(phenylamino)benzophenone (Compound 103),
2-Chloro-4-(2-methoxy-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 104),
2-Chloro-4-(2-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 105),
2-Chloro-4-(2-chloro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 106),
4-(2-tert-Butyoxy-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 107),
2-Chloro-4-(2-hydroxy-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 108),
2-Chloro-4-(3-chloro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 109),
2-Chloro-4-(2-[1,1,1-trifluoromethyl]-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 110),
4-(4-Bromo-2,5-difluoro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 111),
2-Chloro-4-(2-ethyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 112),
2-Chloro-4-(3-[1,1,1-trifluoromethyl]phenylamino)-2xe2x80x2-methylbenzophenone (Compound 113),
2-Chloro-2xe2x80x2-methyl-4-(2-phenyl-phenylamino)benzophenone (Compound 114),
2-Chloro-2xe2x80x2-methyl-4-(3-phenyl-phenylamino)benzophenone (Compound 115),
2-Chloro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 116),
2-Chloro-2xe2x80x2-methyl-4-(3-methyl-phenylamino)benzophenone (Compound 117),
2-Chloro-4-(3-methoxy-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 118),
2-Chloro-4-(4-chloro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 119),
2-Chloro-2xe2x80x2-methyl-4-(4-phenyl-phenylamino)benzophenone (Compound 120),
4-(4-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 121),
4-(4-Bromo-3-fluoro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 122),
4-(2-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 123),
2-Chloro-4-(4-chloro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 124),
2-Chloro-4-(4-chloro-3-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 125),
2-Chloro-4-(3-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 126),
2-Chloro-4-(3,5-difluoro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 127),
4-(3-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 128),
2-Chloro-4-(3,4-difluoro-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 129),
2-Chloro-4-(5-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 130),
2-Chloro-4-(3-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 131),
Ethyl 2-[[3-chloro-4-(2-methylbenzoyl)]phenylamino]benzoate (Compound 132),
2-Chloro-3xe2x80x2-fluoro-4(4fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 133),
2-[[3-Chloro-4-(2-methylbenzoyl)]phenylamino]benzoic acid (Compound 134),
2-Chloro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 135),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 136),
4-(4-Bromo-2-chloro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 137),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-methoxy-2xe2x80x2-methylbenzophenone (Compound 138),
4-(4-Bromo-2-methyl-phenylamino)-2,4xe2x80x2-dichloro-2xe2x80x2-methylbenzophenone (Compound 139),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-fluoro-2xe2x80x2-methylbenzophenone (Compound 140),
4-(4-Bromo-2-methyl-phenylamino)-2-fluoro-2xe2x80x2-methylbenzophenone (Compound 141),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro--2xe2x80x2,5xe2x80x2-dimethyl-benzophenone (Compound 142),
2-Chloro-4-(4-cyano-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 143),
4-(4-Bromo-2-methyl-N-ethyl-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone (Compound 144),
2-Chloro-4-(4-bromo-2-methyl-phenylamino)-4xe2x80x2-ethoxy-2xe2x80x2-methylbenzophenone (Compound 145),
2,3xe2x80x2-Dichloro-4-(4-bromo-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone (Compound 146),
and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
Compounds of formula Ia wherein X=S and wherein R1, R2, R3, R4, and R5 have the meanings specified for formula I, and compounds of formula Ib wherein X=Nxe2x80x94OH and wherein R1, R2, R3, R4, and R5 have the meanings specified for formula I are also generally preferred 
Specific compounds of formula Ia are:
2-[[3-Chloro-4-(2-methyl(thiobenzoyl))]phenylamino]benzonitrile (Compound 301),
2-Chloro-2xe2x80x2-methyl-4-(2-methyl-phenylamino)(thiobenzophenone) (Compound 302),
2-Chloro-2xe2x80x2-methyl-4-(phenylamino)(thiobenzophenone) (Compound 303),
2-Chloro-4-(2-methoxy-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 304),
2-Chloro-4-(2-fluoro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 305),
2-Chloro-4-(2-chloro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 306),
4-(2-tert-Butyoxy-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 307),
2-Chloro-4-(2-hydroxy-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 308),
2-Chloro-4-(3-chloro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 309),
2-Chloro-4-(2-[1,1,1-trifluoromethyl]-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 310),
4-(4-Bromo-2,5-difluoro-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 311),
2-Chloro-4-(2-ethyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 312),
2-Chloro-4-(3-[1,1,1-trifluoromethyl]phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 313),
2-Chloro-2xe2x80x2-methyl-4-(2-phenyl-phenylamino)(thiobenzophenone) (Compound 314),
2-Chloro-2xe2x80x2-methyl-4-(3-phenyl-phenylamino)(thiobenzophenone) (Compound 315),
2-Chloro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 316),
2-Chloro-2xe2x80x2-methyl-4-(3-methyl-phenylamino)(thiobenzophenone) (Compound 317),
2-Chloro-4-(3-methoxy-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 318),
2-Chloro-4-(4-chloro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 319),
2-Chloro-2xe2x80x2-methyl-4-(4-phenyl-phenylamino)(thiobenzophenone) (Compound 320),
4-(4-Bromo-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 321),
4-(4-Bromo-3-fluoro-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 322),
4-(2-Bromo-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 323),
2-Chloro-4-(4-chloro-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 324),
2-Chloro-4-(4-chloro-3-fluoro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 325),
2-Chloro-4-(3-fluoro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 326),
2-Chloro-4-(3,5-difluoro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 327),
4-(3-Bromo-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 328),
2-Chloro-4-(3,4-difluoro-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 329),
2-Chloro-4-(5-fluoro-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 330),
2-Chloro-4-(3-fluoro-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 331),
Ethyl 2-[[3-chloro-4-(2-methyl(thiobenzoyl))]phenylamino]benzoate (Compound 332),
2-Chloro-3xe2x80x2-fluoro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 333),
2-[[3-Chloro-4-(2-methyl(thiobenzoyl))]phenylamino]benzoic acid (Compound 334),
2-Chloro-4-(4-fluoro-2-methyl-N-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 335),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 336),
4-(4-Bromo-2-chloro-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 337),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-methoxy-2xe2x80x2-methyl(thiobenzophenone) (Compound 338),
4-(4-Bromo-2-methyl-phenylamino)-2,4xe2x80x2-dichloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 339),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-fluoro-2xe2x80x2-methyl(thiobenzophenone) (Compound 340),
4-(4-Bromo-2-methyl-phenylamino)-2-fluoro-2xe2x80x2-methyl(thiobenzophenone) (Compound 341),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro--2xe2x80x2,5xe2x80x2-dimethyl-(thiobenzophenone) (Compound 342),
2-Chloro-4-(4-cyano-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 343),
4-(4-Bromo-2-methyl-N-ethyl-phenylamino)-2-chloro-2xe2x80x2-methyl(thiobenzophenone) (Compound 344),
2-Chloro-4-(4-bromo-2-methyl-phenylamino)-4xe2x80x2-ethoxy-2xe2x80x2-methyl(thiobenzophenone) (Compound 345),
2,3xe2x80x2-Dichloro-4-(4-bromo-2-methyl-phenylamino)-2xe2x80x2-methyl(thiobenzophenone) (Compound 346),
and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
Specific compounds of formula Ib are:
2-[[3-Chloro-4-[(hydroxyimino)(2-methylphenyl)methyl]]phenylamino]benzonitrile (Compound 401),
2-Chloro-2xe2x80x2-methyl-4-(2-methyl-phenylamino)benzophenone oxime (Compound 402),
2-Chloro-2xe2x80x2-methyl-4-(phenylamino)benzophenone oxime (Compound 403),
2-Chloro-4-(2-methoxy-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 404),
2-Chloro-4-(2-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 405),
2-Chloro-4-(2-chloro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 406),
4-(2-tert-Butyoxy-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 407),
2-Chloro-4-(2-hydroxy-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 408),
2-Chloro-4-(3-chloro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 409),
2-Chloro-4-(2-[1,1,1-trifluoromethyl]-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 410),
4-(4-Bromo-2,5-difluoro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 411),
2-Chloro-4-(2-ethyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 412),
2-Chloro-4-(3-[1,1,1-trifluoromethyl]phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 413),
2-Chloro-2xe2x80x2-methyl-4-(2-phenyl-phenylamino)benzophenone oxime (Compound 414),
2-Chloro-2xe2x80x2-methyl-4-(3-phenyl-phenylamino)benzophenone oxime (Compound 415),
2-Chloro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 416),
2-Chloro-2xe2x80x2-methyl-4-(3-methyl-phenylamino)benzophenone oxime (Compound 417),
2-Chloro-4-(3-methoxy-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 418),
2-Chloro-4-(4-chloro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 419),
2-Chloro-2xe2x80x2-methyl-4-(4-phenyl-phenylamino)benzophenone oxime (Compound 420),
4-(4-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime(Compound 421),
4-(4-Bromo-3-fluoro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 422),
4-(2-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 423),
2-Chloro-4-(4-chloro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 424),
2-Chloro-4-(4-chloro-3-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 425),
2-Chloro-4-(3-fluoro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 426),
2-Chloro-4-(3,5-difluoro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 427),
4-(3-Bromo-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 428),
2-Chloro-4-(3,4-difluoro-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 429),
2-Chloro-4-(5-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 430),
2-Chloro-4-(3-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 431),
Ethyl 2-[[3-chloro-4-[(hydroxyimino)(2-methylphenyl)methyl]]phenylamino]benzoate (Compound 432),
2-Chloro-3xe2x80x2-fluoro-4-(4-fluoro-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 433),
2-[[3-Chloro-4-[(hydroxyimino)(2-methylphenyl)methyl]]phenylamino]benzoic acid (Compound 434),
2-Chloro-4-(4-fluoro-2-methyl-N-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 435),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 436),
4-(4-Bromo-2-chloro-phenylamino)-2-chloro-2xe2x80x2-methylbenzophenone oxime (Compound 437),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-methoxy-2xe2x80x2-methylbenzophenone oxime (Compound 438),
4-(4-Bromo-2-methyl-phenylamino)-2,4xe2x80x2-dichloro-2xe2x80x2-methylbenzophenone oxime (Compound 439),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-4xe2x80x2-fluoro-2xe2x80x2-methylbenzophenone oxime (Compound 440),
4-(4-Bromo-2-methyl-phenylamino)-2-fluoro-2xe2x80x2-methylbenzophenone oxime (Compound 441),
4-(4-Bromo-2-methyl-phenylamino)-2-chloro-2xe2x80x2,5xe2x80x2-dimethyl-benzophenone oxime (Compound 442),
2-Chloro-4-(4-cyano-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 443),
4-(4-Bromo-2-methyl-N-ethyl-phenylamino)-2-chloro-2xe2x80x2-methyl benzophenone oxime (Compound 444),
2-Chloro-4-(4-bromo-2-methyl-phenylamino)-4xe2x80x2-ethoxy-2xe2x80x2-methylbenzophenone oxime (Compound 445),
2,3xe2x80x2-Dichloro-4-(4-bromo-2-methyl-phenylamino)-2xe2x80x2-methylbenzophenone oxime (Compound 446),
and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
The compounds of formulae I, VII, Ia, and Ib can be used in the form of their salts which are formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, maleic acid, these examples being considered as non-limiting for the invention.
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C1-C3)alkyl, (C1-C5)alkyl, (C5)alkyl, (C6-C10)alkyl, (C6-C15)alkyl, methyl, ethyl, n-propy isobutyl, sec-butyl, and t-butyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the general formula CnH2n+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
xe2x80x9cOlefinic groupxe2x80x9d refers to a straight or branched acyclic hydrocarbon having one or more carbon-carbon double bonds of either E or Z stereochemistry where applicable, and having the number of carbon atoms specified. The term includes, for example, (C2-C15)olefinic group, preferably a (C2-C15)alkenyl; (C2-C3)olefinic group, preferably a (C2-C3)alkenyl; vinyl; allyl; 1-butenyl; 2-butenyl; and 2-methyl2-propenyl. Olefinic groups having only one carbon-carbon double bond, herein called alkenyl, are preferred.
xe2x80x9cAlkoxyxe2x80x9d refers broadly to a radical of the formula xe2x80x94OR, where R is alkyl as defined above, for example (C1-C3)alkoxy, (C1-C2)alkoxy, methoxy, ethoxy, n-propoxy, and the like.
xe2x80x9c(C1-C3)alkylthioxe2x80x9d refers broadly to a radical of the formula xe2x80x94SR, where R is alkyl as defined above and includes methylthio, ethylthio, n-propylthio, and 2-propylthio.
xe2x80x9c(C1-C6)alkylaminoxe2x80x9d refers broadly to a radical of the formula xe2x80x94NHR or xe2x80x94NR2, where R is alkyl as defined above having from 1-6 carbon atoms and includes, for example, methylamino, dimethylamino, di-(n-propyl)amino, and n-butyl(ethyl)amino.
xe2x80x9c(C1-C3)alkoxycarbonylxe2x80x9d refers broadly to a radical of the formula xe2x80x94COOR, where R is alkyl as defined above and includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and i-propoxycarbonyl.
xe2x80x9c(C3-C10)monocyclic hydrocarbon groupxe2x80x9d includes the saturated cycloalkanes and unsaturated cyclic olefins, such as cycloalkenes having one endocyclic double bond, and having from 3-10 carbon atoms, and includes, for example, (C3-C8)cycloalkyl, cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl, (C3-C10)cycloalkene group, and (C3-C8)cycloalkene group. Specific examples are cycloprop-2-enyl, cyclobut-2-enyl, cyclopent-2-enyl, cyclohex-3-enyl, and cyclonon-4-enyl.
xe2x80x9cAminoxe2x80x9d means the group xe2x80x94NH2.
xe2x80x9cCarbamoylxe2x80x9d refers to the group xe2x80x94CONH2, xe2x80x94CONHR, and xe2x80x94CONRRxe2x80x2 where R and Rxe2x80x2 represent alkyl as defined above.
xe2x80x9cCarboxyxe2x80x9d refers broadly to a radical of the formula xe2x80x94COOH.
xe2x80x9cHalogenxe2x80x9d means the same or different of fluoro, chloro, bromo, and iodo; fluoro, chloro, and bromo being preferred.
Pharmacological Methods
To study the effect of the compound of the present invention in vitro the inhibition of the IL-1xcex2 and TNF-xcex1 secretion was measured using the following procedure:
Cytokine production was measured in the media from lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells. The mononuclear cells were isolated from human peripheral blood by Lymphoprep(copyright) (Nycomed, Norway) fractionation and suspended in RPMI 1640 (growth medium) with foetal calf serum (FCS, 2%), at a concentration of 5xc3x97105 cells/ml. The cells were incubated in 24-well tissue culture plates in 1 ml aliquots. Test compounds were dissolved in dimethylsulfoxide (DMSO, 10 mM) and were diluted with the medium. Compounds were added to the cells for 30 minutes, then LPS (1 mg/ml final concentration) was added. The plates were incubated for 18 hours, and the concentration of IL-1xcex2 and TNF-xcex1 in the medium was determined by enzyme-linked immunosorbent assays. The median inhibitory concentrations (IC50) of the compounds were calculated. The results are shown in Table 1.
The compounds of the present invention also show similar activities in the ability to inhibit PMN (polymorphonuclear) superoxide secretion which is also indicative of potentially useful anti-inflammatory drugs. The compounds were tested using the following procedure:
Human polymorphonuclear (PMN) granulocytes were isolated from human blood by dextran sedimentation, Lymphoprep(copyright) fractionation and hypotonic lysis of contaminating erythrocytes.
Superoxide anion generation was measured as the superoxide dismutase inhibitable reduction of ferricytochrome C (Madhu, S. B. et al, Inflammation, 16, 241, (1992)). The cells were suspended in Hanks"" balanced salt solution, and incubated for 10 minutes at 37xc2x0 C. with test compounds. The cells were primed by the addition of TNF-xcex1 (3 ng/ml final concentration) for 10 minutes, and then ferricytochrome C, (final concentration 750 xcexcg/ml), bovine serum albumin (BSA, final concentration 1 mg/ml) and formyl-methionyl-leucyl-phenylalanine (fMLP, final concentration 10xe2x88x927 M) were added for 3 minutes. The cells were chilled on ice, and were spun down. The optical densities in the cell-free supernatant was measured in a spectrophotometer. The median inhibitory concentration (IC50) of the compounds was calculated. The results are shown in Table 1.
These results show that the compounds of the present invention are able to inhibit the production of IL-1xcex2, TNF-xcex1 and PMN-superoxide, and showing a pharmacological activity comparable to a reference compound, thus making them potentially useful in the treatment of inflammatory diseases. It appears from the results shown in Table 1 that some of the compounds of the invention are more selective for one of these inflammatory cytokines than for the other two. This may be an advantage in certain therapeutic situations where a more selective cytokine inhibition is indicated.
To study the compounds of the present invention in vivo the 12-O-tetradecanoylphorbol-13-acetate TPA) induced murine chronic skin inflammation model can be used (De Young, L. M. et al, Agents Actions, 26, 335-341 (1989); Carlson, R. P. et al, Agents Actions, 17, 197-204 (1985); Alford, J. G. et al, Agents Action, 37, (1992); Stanley, P. L. et al, Skin Pharmacol, 4, 262-271 (1991)), cf. description of method in WO 98/32730 hereby incorporated by reference. These results show that the compounds of the present invention are of the same potency compared to known reference compounds, e.g. hydrocortisone with its known side effects, whereas the compounds of the present invention are well tolerated and are non-toxic. Some members of the present class of compounds show a very low systemic absorption, thus making them especially useful in the treatment of various dermatological diseases. In general, they may be administered by e.g. oral, intravenous, intranasal, topically or transdermal routes.
Method of Preparation
The compounds of th e present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesised using the methods outlined below, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
The novel compounds of formulae I, VII, Ia, and Ib may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognised by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods can be used.
Compounds according to the present invention may be prepared by a process comprising coupling of an amine of the formula III with a bromide, iodide, fluoride, chloride or triflate with the formula II, as shown in scheme 1, where R1, R2, R3, R4, R5, and X are as defined in general formula I, except that an substituents or functional groups which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed. The coupling reaction is carried out using any of the methods for the formation of diphenylamines known to one skilled in the art of organic synthesis. The preferred method is the palladium catalysed amination method which comprises coupling of an amine with an arylhalogenide (or aryltriflate) in the presence of a base, a suitable Pd source, and a suitable phosphine ligand in an inert solvent. The palladium compound used in the process is not particularly limited, and as specific examples are palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O). The preferred ligands include, but are not limited to, racemic or non-racemic 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (hereinafter refered to as BINAP), tri-o-tolylphosphine, tri-tert-butylphosphine, 1,1xe2x80x2-bis(diphenylphosphino)-ferrocene, bis[(2-diphenylphosphino)phenyl]ether (DPEphos), 2-dicyclohexylphosphanyl-2xe2x80x2-dimethylaminobiphenyl, 2-(di-tert-butylphosphino)biphenyl, and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (Xantphos). The amount of palladium and ligand used in this process is typically in the range 0.1 to 10% by mole relative to the amount of the aromatic halide (or triflate) used. Especially sodium-tert-butoxide (NaOt-Bu) and caesium carbonate (Cs2CO3) have proven to be the best bases in this process, but other bases may be used as well. The reaction is typically performed at elevated temperature (80-120xc2x0 C.) in inert solvents like 1,4-dioxane, toluene, benzene and tetrahydrofurane under an inert atmosphere like argon or nitrogen. 
Compounds according to the present invention in which R4 is not hydrogen may be prepared by a process comprising coupling of an amine of the formula I (R4=H) with an alkylating agent, as shown in scheme 1, where R1, R2, R3, R5, and X are as defined in general formula I, except that any substituents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed. Typically alkylating agents of the general formula Rxe2x80x94Y include, but are not limited to, iodides (Y=I), bromides (Y=Br), chlorides (Y=Cl) and sulfonates (L=OSO2Rxe2x80x2, where Rxe2x80x2 represents methyl, trifluoromethyl or 4-methylphenyl).
Compounds according to the present invention may in special cases be prepared by a simple functional group interconversion (FGI), meaning a standard process, known to those skilled in the art of organic synthesis, where a functional group in compounds with the general formula I is transformed into a different functional group in one or more synthetic steps, leading to a new compound with the general formula I. Examples of such processes are, but are not limited to, hydrolysis of an ester to give an acid under basic conditions; deprotection of a methylether to give a phenol by treatment with e.g. borontribromide (BBr3); and catalytic hydrogenation of an olefin to give a saturated hydrocarbon. Compounds according to the present invention with the general formula I where X=S may be prepared from the ketone (with the general formula I, C=O) by such an FGI process, by using one of the many thiocarbonylating reagent, known to those skilled in the art of organic synthesis. Examples of such thiocarbonylating reagents include, but are not limited to, phosphorous pentasulfide (P4S10), or Lawesson""s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) or the like. Compounds according to the present invention with the general formula I where X=Nxe2x80x94OH may be prepared from the ketone (with the general formula I, C=O) by treatment with hydroxylamine, or a protected derivative thereof followed by deprotection, in an appropriate solvent like e.g. pyridine or methanol.
Compounds according to the present invention with the general formula III may be prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in scheme 2. The key step comprising coupling of a bromide (or iodide) with the general formula VI with an acid chloride with the general formula V to afford the benzophenone with the general formula IV. This compound IV may then be reduced to the corresponding amine with the general formula III by treatment with standard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate; hydrogen, ammonium formiate, or hydrazine hydrate and a catalytic amount of palladium on carbon. The coupling reaction is done by transforming the bromide (VI) into a reactive organometallic intermediate, e.g. by treatment with butyllithium to afford the lithium derivative or by treatment with magnesium to afford the magnesium derivative. 
The reactivity of this intermediate is then modulated by transmetalation to e.g. zinc, by treatment with ZnCl2, ZnBr2, or Znl2. This organozinc compund is then coupled with the acid chloride, with the general formula V, under the influence of a palladium(O) complex in catalytic amount. Examples of such catalyst include but are not particularly limited to tetrakis(triphenylphosphine)palladium(O), tetrakis(triphenylarsine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), or benzylchlorobis(triphenylphosphine)palladium(II).
As shown on scheme 2 compounds with the general formula IV (X=O) may be transformed by an FGI process to give compounds with the general formula IV (X=S or X=Nxe2x80x94OH) as described above. This is only to illustrate the flexibility in the synthesis and in general the described sequence of processes is only one of many possible strategies for the synthesis of compound of the present invention. That is, it may be more advantageous in some cases to alter the sequence of the processes described above. The described sequence of processes is not considered as being limited for the preparation of the compounds of the present invention with the general formula I and alteration of the reaction sequence is an obvious alternative for those skilled in the art of organic synthesis.
The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned diseases.
The amount required of a compound of formula I, VII, Ib and Ia (hereinafter referred to as the active compound or active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of an active compound for systemic treatment is 0.1 to 200 mg/kg bodyweight, the most preferred dosage being 0.2 to 50 mg/kg of mammal bodyweight, administered one or more times daily.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1% to 100% by weight of the formulation. Conveniently, dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient. For topical administration, the active ingredient preferably comprises from 1% to 20% by weight of the formulation but the active ingredient may comprise as much as 50% w/w. Formulations suitable for nasal or buccal administration may comprise 0.1% to 20% w/w. for example about 2% w/w of active ingredient.
By the term xe2x80x9cdosage unitxe2x80x9d is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations, both for veterinary and human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.
Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.
In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients.
The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance glucocorticoids, vitamin D analogues, anti-histamines, platelet activating factor (PAF) antagonists, anticolinergic agents, methyl xanthines, xcex2-adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
The novel compounds of the invention are of value in the human and veterinary practice as systemic and topical therapeutic agents for the treatment and prevention of diseases. The novel compounds show anti-acne properties and, i.a., anti-inflammatory and cytokine regulating effects possibly due to MAP kinase inhibition, and are useful in the treatment and prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn""s disease), proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis or acne; uveitis, septic shock, AIDS, and osteoporosis.